The purpose of this project is to clarify the relationship between structure and antitumor activity in the actinomycin series. This includes structure determination of some novel actinomycins and a study of the secondary structure (conformation) of various actinomycins by nuclear magnetic resonance techniques. Also, comparative physicochemical studies of different actinomycins in complexation with nucleotides will be undertaken. The proton NRM studies will be extended to several new actinomycins containing various proline analogues in place of one or both of the proline moieties of actinomycin D. An X-ray crystallographic analysis of actinomycin III will be undertaken. This actinomycin has proline in one peptide moeity and sarcosine in the proline site of the other peptide, so that any conformational differences between the two cyclopeptides can be investigated. Studies will be initiated on the complexation of various actinomycins with guanine-containing mono- and dinucleotides as models for the actinomycin-DNA interaction. This will be done principally by Fourier-transform proton NMR and will compare actinomycins containing proline, sarcosine, pipecolic acid and azetidine-2-carboxylic acid in the proline site. BIBLIOGRAPHIC REFERENCES: E. Katz, K.T. Mason and A.B. Mauger, "3-Hydroxy-5-methylproline, a New Amino Acid Identified as a Component of Actinomycin Z1" Biochem. Biophys. Res. Comm. "63," 502 (1975). A.B. Mauger, "The Thermal Degradation of Actinomycins to Dioxopiperazines", J. Chem. Soc. Perkin I, 1320 (1975).